As a process of the synthesis of N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine are hitherto known (a) a process wherein after conducting a Michael addition reaction of N6-trifluoroacetyl-L-lysine to ethyl β-benzoylacrylate, carbonyl group in the benzoyl portion is converted into methylene group by catalytic reduction (JP-B-4-4308), (b) a process wherein ethyl 2-oxy-4-phenylbutyrate and N6-trifluoroacetyl-L-lysine are subjected to reductive amination (CN-B-1053437), and the like.
Besides the desired N2-(1(S)-ethoxycarbonyl-3-phenyl-propyl)-N6-trifluoroacetyl-L-lysine, various impurities having analogous structures are by-produced or remain in the above-mentioned processes.
These impurities are, for instance, the diastereomer, i.e., N2-(1(R)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine of the formula (2):
a cyclohexyl derivative, i.e., N2-(1(S)-ethoxycarbonyl-3-cyclohexyl-propyl)-N6-trifluoroacetyl-L-lysine of the formula (3):
a carboxyl derivative, i.e., N2-(1(S)-carboxy-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine of the formula (4):
an ester derivative, i.e., N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine ester of the formula (5):
wherein R is an alkyl group, ethyl phenylbutyrate, and the like.
The diastereomer (2) is produced when the stereoselectivity of the reaction is insufficient. The cyclohexyl derivative (3) is produced by hydrogenation of benzene ring when the catalytic reduction is conducted. The carboxyl derivative (4) is produced by hydrolysis or by cleavage of the ester moiety during the catalytic reduction. The ester derivative (5) is a compound that the terminal carboxyl group of the desired product is converted into an ester group, and is produced by a side reaction. In the formula (5), R denotes an alkyl group such as methyl group or ethyl group, especially a lower alkyl group having 1 to 4 carbon atoms. Also, ethyl phenylbutyrate is produced by reduction of ethyl β-benzoylacrylate.
Needless to say, incorporation of these structure analogous impurities and so on into the product N2-(1(S)-ethoxycarbonyl-3-phenyl-propyl)-N6-trifluoroacetyl-L-lysine should be prevented as much as possible, and for this purpose, a good purification process is required.
As a process of the purification of N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine is hitherto known a process wherein crystallization is conducted from an ethanol/water mixed solvent whereby the diastereomer is removed (JP-B-4-4308).
However, as a result of present inventors' investigation, it was found that this purification process has large problems on industrial production that the physical properties of the obtained crystals are bad, the filtering property is bad, the filtered cake cracks and therefore it is not possible to conduct washing, resulting in low quality, the obtained wet matter has a high liquid content and therefore is hard to be dried, and the crystallization concentration is not necessarily high.
Accordingly, an object of the present invention is to provide a process of the purification suitable for practice on an industrial scale for obtaining N2-(1(S)-ethoxycarbonyl-3-phenylpropyl)-N6-trifluoroacetyl-L-lysine having a high quality, namely high purity and good physical properties of crystals, in a high yield and a high productivity.